The invention generally relates to the chemotherapy or treatment of leishmaniasis. Leishmania are well known intra-cellular protozoan parasites which may give rise to serious infections in man. The organisms are transmitted by the "bite" of an infected sandfly, and invade the reticulo-endothelial system (RES). The parasites are highly successful in their ability to grow and multiply in the very tissues of the vertebrate host which are responsible for reaction to invading organisms. Expectedly, such location of Leishmania renders difficult a satisfactory approach to chemotherapy, and there is highly complex inter-play between parasites and cellular immune responses of the host. In the RES, the parasites lie within the host macrophage for at least part of their life cycle. Fusion of host cell secondary lysosomes with the parasitophorous vacuoles apparently occurs without preventing subsequent multiplication of the Leishmania. Such fusion may provide means for access for nutrients to the parasite, but also exposes the parasite to host antibodies and lysosomal enzymes. In man, the result of successful invasion of the spleen and liver by Leishmania donovani most frequently is death. Scarring of the skin may be the sole manifestation of infection with Leishmania tropica and allied dermatotropic organisms (as, Leishmania aethiopica, L. mexican, L. peruviana, and L. guyanensis). Intermediate in severity are invasions of muco-cutaneous tissues by Leishmania braziliensis. There are considerable differences among various animals in their response to leishmanial infections, however, a satisfactory animal model for laboratory trials has been found in Leishmania donovani infections in the gold hamster.
The L. donovani-hamster model has been used widely to assess candidate drugs for anti-leishmanial effects. Unfortunately, relatively few drugs have been found to show appreciable activity on screening, and fewer yet have merited trial in man. Antimony drugs are a mainstay for treatment despite evaluation of diverse types both in the laboratory and in clinical trials. Pentavalent compounds of antimony are better tolerated than trivalent antimonials, yet severe toxic side effects may occur, in particular, among poorly nourished patients. Toxicity of such drugs may affect the liver (hepatitis), kidneys (nephritis), or the heart (myocarditis). Of these toxic effects, myocarditis is the greatest and most common problem. Of the antimonial drugs, one widely used in the clinic is the N-methyl glucamine salt of antimonic acid, frequently called meglumine antimoniate. That compound has been presently employed as a reference drug in evaluation of compounds in the L. donovani-hamster test.
Quinoline derivatives are known to have chemotherapeutic effects against diverse parasites of man. Expecially noteworthy potency against malaria parasites has been demonstrated among 4-aminoquinoline and 8-aminoquinoline structures. In the case of 8-aminoquinoline derivatives, but not 4-aminoquinolines, anti-leishmanial effects have been demonstrated in the Leishmania donovani test in the hamster. Such activity against Leishmania shown by the 8-aminoquinolines is a distinct aspect of anti-parasitic effects, and not related to (e.g.) antimalarial profile thereof. Among series of 8-aminoquinolines, certain 8-amino-6-methoxy-4-methylquinolines (otherwise called 8-amino-6-methoxy lepidines) have been identified as markedly more effective than allied compounds lacking the 4-methyl grouping: K. E. Kinnamon, et a., Am. J. Trop. Med. Hyg., 27, 751-757 (1978). The 8-amino-6-methoxylepidines are also subject of the co-pending U.S. patent application Ser. No. 886,024 (Mar. 13, 1978) of K. E. Kinnamon now U.S. Pat. No. 4,209,519. In such work, meglumin antimoniate was used as reference drug. Activity was expressed through use of G index derived from the expression ##EQU1## wherein SD.sub.90 refers to the dose causing 90% suppression of L. donovani parasites (amastigote form) present in the livers of infected hamsters. Under standard test conditions--as described by W. L. Hanson, et al. in International J. Parasitol., 7, 443-447 (1977)--primaquine (which is the drug of choice as a radical curvative antimalarial agent) had G index=2.1; 4-methyl primaquine had G index=33. The most active compound was 8-(6-diethylaminohexylamino)-6-methoxylepidine, which had G index=474 by intramuscular route and 708 by oral route. 8-Aminoquinolines have thus been established as effective anti-leishmanial agents in a standard test system.